The present invention relates to compounds having pharmacological activity toward the 5-HT7 receptor. Pharmaceutical compositions and methods for their use in the treatment of CNS disorders are described.
The 5-HT7 receptor is the most recent addition to the burgeoning family of 5-HT receptors. 5-HT7 receptors have been cloned from rat, mouse, guinea pig, and human cDNA and exhibit a high degree of interspecies homology, (approximately 95%) but a low sequence homology with other 5-HT receptors ( less than 40%). The pharmacological profile of this receptor is unique yet consistent across species. Thus, high 5-HT7 receptor affinity is observed from 5-CT, 5-HT, 5-MeOT, and methiothepin, moderate affinity for 8-OHDPAT, clozapine, and ritanserin, and low affinity for pindolol, sumatriptan, and buspirone. Recent data have demonstrated the existence of four 5-HT7 splice variants in humans and three in rat (Heidmann, et al., J. Neurochem., 1997, 68, 1372-1381). Preliminary pharmacological comparison of the long (5-HT7a) and short (5-HT7b) forms of the receptor have revealed no substantial differences in receptor binding affinity (Jasper et al., J. Pharmocol., 1997, 120, 298). 5-HT7 receptors are positively coupled to adenylate cyclase when expressed in cell lines, native guinea pig hippocampus, and cultured vascular smooth muscle cells.
The greatest abundance of 5-HT7 mRNA is found in the brain where it is discretely located within thalamus, hypothalamus, and various limbic and cortical regions. Autoradiographic techniques confirm that the distribution of 5-HT7 receptor binding sites in rat and guinea pig brain matches, to a large extent, the mRNA distribution (To, et al., J. Pharmocol., 1995, 115, 107-116).
Preliminary data support that the 5-HT7 receptor may be involved in the pathophysiology of sleep disorders, depression, (Schwartz, et al., Adv. Int. Med. 1993, 38, 81-106) and schizophrenia (Roth, et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403-1410). The 5-HT7 receptor stimulation has caused relaxation of the blood vessels in monkey (Leung, et al. Br. J. Pharmocol., 1996, 117, 926-930), dog (Cushing, et al. J. Pharmocol. Exp. Ther., 1996, 277, 1560-1566) and rabbit (Martin, et al., Br. J. Pharmocol., 1995, 114, 383). Therefore, the therapeutic utility of 5-HT7 receptor ligands requires the discovery of selective therapeutic agents. The present invention discloses novel 5-HT7 receptor antagonists.
Accordingly, one object of the present invention is to provide novel inhibitors of the 5-HT7 receptor or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating central nervous system disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt forms thereof, wherein R1, X, Y, n and A are defined below, are effective 5-HT7 inhibitors.
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula (I): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
R1 is selected from a C6-10 carbocyclic aromatic residue substituted with 1-3 R1a, and a 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S substituted with 0-2 R1a;
R1a is independently selected at each occurrence from halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3 and xe2x80x94CF2CF3;
X is selected from xe2x80x94S(O)pxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x80x94CH(OC(O)CH3)xe2x80x94, xe2x80x94NR4axe2x80x94, xe2x80x94S(O)2NR4xe2x80x94 and a five membered saturated, partially saturated or unsaturated ring containing 0-2 heteroatoms selected from the group consisting of O and N;
with the proviso that when X is a five membered saturated, partially saturated or unsaturated ring containing 0-2 heteroatoms selected from O and N, R1 may be an unsubstituted C6-10 carbocyclic aromatic residue;
R4 is selected from hydrogen and C1-6 alkyl;
R4a is taken together with R1 to form a 5 or 6-membered fused heterocyclic ring containing 1-2 heteroatoms selected from O or N, and substituted with 1 or 2 carbonyl groups;
Y is C1-3 alkylene;
A is selected from a 5 or 6 membered saturated, partially saturated or unsaturated ring which contains from 0-1 heteroatoms selected from N, O and S substituted with 0-3 R5, napthyl substituted with 0-3 R5, and napthyl fused with ring B substituted with 0-3 R5;
R5 is selected from C1-5 alkyl, halo and xe2x80x94OCH3;
n is selected from 1, 2, and 3; and
p is selected from 0, 1, and 2.
[2] In a preferred embodiment, the present invention provides novel compounds, wherein:
R1 is phenyl substituted with 1-3 R1a;
R1a is selected independently at each occurrence from halo, xe2x80x94CN, xe2x80x94CF3 and xe2x80x94CF2CF3;
X is selected from xe2x80x94S(O)2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR4axe2x80x94, xe2x80x94C(O)xe2x80x94, isoxazolyl and isoxazolinyl;
R4a is taken together when R1 is phenyl to form a 5 membered fused cyclic urea;
Y is propylene;
A is selected from phenyl substituted with 0-3 R5, napthyl substituted with 0-3 R5 and napthyl fused with ring B substituted with 0-3 R5;
R5 is selected independently at each occurrence from C1-5 alkyl, halo and xe2x80x94OCH3; and
n is selected from 1 and 2.
[3] In a more preferred embodiment, the present invention provides novel compounds, wherein:
R1 is phenyl substituted with 1-3 R1a;
R1a is selected independently at each occurrence from para-halo and meta-fluoro;
X is selected from xe2x80x94S(O)2xe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94C(O)xe2x80x94;
Y is propylene;
A is phenyl substituted with 0-2 R5;
R5 is selected independently at each occurrence from C1-5 alkyl, halo and xe2x80x94OCH3; and
n is selected from 1 and 2.
[4] In a further more preferred embodiment, the present invention provides novel compounds, wherein:
R1 is phenyl substituted with 1-3 R1a;
R1a is meta-fluoro;
X is selected from xe2x80x94S(O)2xe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94C(O)xe2x80x94;
Y is propylene;
A is phenyl substituted with 0-2 R5;
R5 is selected independently at each occurrence from C1-5 alkyl, halo and xe2x80x94OCH3; and
n is selected from 1 and 2.
[5] In an even further more preferred embodiment, the present invention provides a compound selected from the group:
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))isoindole,
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-hydroxybutyl)) isoindole,
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-acetoxybutyl)) isoindole,
2-((4-(4-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl)) benz[f]isoindole,
2-((4-(4-Pyridyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
2-((4-(3-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))-1H-benz[de] isoquinoline,
2-((4-Oxo-4-(2-thienyl)butyl))-1,2,3,4-tetrahydroisoquinoline,
6,7-Dimethoxy-2-((4-(4-fluorophenyl)oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
2-((3-(1,3-Dihydro-2H-benzimidazol-2-one)-1-ylpropyl))-1,2,3,4-tetrahydroisoquinoline,
2-(3-Phenylisoxazol-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline,
(+/xe2x88x92)-2-((3-(4-Fluorophenyl)-2-isoxazolin-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline,
1,3-Dihydro-2-((3-(4-fluorophenoxy)propyl))isoindole,
2-((3-(4-Fluorophenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline,
1,3-Dihydro-2-((3-(4-fluorophenylthio)propyl))isoindole,
1,3-Dihydro-2-((3-(4-fluorophenylsulfonyl)propyl)) isoindole,
2-((3-(4-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline
2-((3-(3-Fluorophenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline
2-((3-(3-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline
1,3-Dihydro-2-((4-(4-pyridyl)-4-oxobutyl))isoindole,
1,3-Dihydro-2-((4-(3-pyridyl)-4-oxobutyl))isoindole,
1,3-Dihydro-2-((4-(4-nitrophenyl)-4-oxobutyl))isoindole,
1,3-Dihydro-2-((4-(3-nitrophenyl)-4-oxobutyl))isoindole,
1,3-Dihydro-2-((4-(2-thienyl)-4-oxobutyl))isoindole,
1,3-Dihydro-2-((4-(3-thienyl)-4-oxobutyl))isoindole,
2-((4-(3-Pyridyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
2-( (4-(4-Nitrophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
2-((4-(3-Nitrophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
2-((4-(3-Thienyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
2-((3-(4-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,
2-((3-(4-Pyridylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,
2-((3-(4-Nitrophenylsulfonyl)propyl) )-1,2,3,4-tetrahydroisoquinoline,
2-((3-(3-Nitrophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,
2-((3-(2-Thienylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,
2-((3-(3-Thienylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,
1,3-Dihydro-2-((1-(3-thienylsulfonyl)propyl))isoindole,
1,3-Dihydro-2-((1-(2-thienylsulfonyl)propyl))isoindole,
1,3-Dihydro-2-((1-(4-fluorophenylsulfonyl)propyl)) isoindole,
1,3-Dihydro-2-((1-(3-fluorophenylsulfonyl)propyl)) isoindole,
1,3-Dihydro-2-((1-(4-nitrophenylsulfonyl)propyl)) isoindole,
1,3-Dihydro-2-((1-(3-nitrophenylsulfonyl)propyl)) isoindole,
1,3-Dihydro-2-((1-(4-pyridylsulfonyl)propyl))isoindole, and
1,3-Dihydro-2-((1-(3-pyridylsulfonyl)propyl))isoindole.
[6] In a second embodiment, the present invention provides a novel compound of formula (II): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
R1 is selected from a C6-10 carbocyclic aromatic residue substituted with 1-3 R1a, and a 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R1a;
R1a is independently selected at each occurrence from (CH2)rOR1d, halo, C1-4 alkyl, (CH2)rxe2x80x94C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCF3, (CH2)rNR1bR1c, (CH2)rSO2R1d, (CH2)rC(O)OH, (CH2)rC(O)OR1d, (CH2)rOC(O)R1d, (CH2)rC(O)R1d, (CH2)rNR1bC(O)R1c, (CH2)rC(O)NR1bR1c, (CH2)rSR1d, (CH2)rCH(xe2x95x90NR1b)NR1bR1c, (CH2)rSO2NR1bR1c, (CH2)rSO2NR1bR1c, (CH2)r(CF2)rCF3 and (CH2)r-phenyl substituted with 0-3 R1e;
R1b and R1c are independently selected at each occurrence from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl and (CH2)r-phenyl substituted with 0-3 R1e;
R1d is independently selected at each occurrence from C1-6 alkyl and (CH2)r-phenyl substituted with 0-2 R1e;
R1e is independently selected at each occurrence from H, xe2x80x94(CH2)rOR1e, halo, C1-4 alkyl, CN, NO2, and xe2x80x94CF3;
R1f is selected from hydrogen and C1-5 alkyl;
R1g is C1-5 alkyl;
X is selected from xe2x80x94CR6R7xe2x80x94, xe2x80x94CR2R3xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2NR4xe2x80x94 and NR4a;
R4 is selected independently at each occurrence from hydrogen, C1-6 alkyl, (CH2)rxe2x80x94C3-7 cycloalkyl, (CH2)r-aryl, and (CH2)r-heteroaryl;
R4a is taken together with R1 to form a 5 or 6-membered fused heterocyclic ring containing 1-2 heteroatoms selected from O and N, substituted with 1 or 2 carbonyl groups;
R6 is selected independently at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)rxe2x80x94C3-6 cycloalkyl, (CH2)r-phenyl, xe2x80x94OH, xe2x80x94OC(O)R6a, C(O)R6a and C(O)OR6a;
R6a is selected independently from C1-6 alkyl, phenyl and benzyl;
R7 is selected from hydrogen and C1-5 alkyl;
A is selected from a 5 or 6 membered saturated, partially saturated or unsaturated ring which contains from 0-1 heteroatoms selected from N, O and S substituted with 0-3 R5, napthyl substituted with 0-3 R5, and napthyl fused with ring B substituted with 0-3 R5;
R5 is selected independently at each occurrence from (CH2)rOR5d, halo, C1-4 alkyl, (CH2)rxe2x80x94C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCF3, (CH2)rNR5bR5c, (CH2)rSO2R5d, (CH2)rC(O)OH, (CH2)rC(O)OR5d, (CH2)rOC(O)R5d, (CH2)rC(O)R5b, (CH2)rNR5bC(O)R5c, (CH2)rC(O)NR5bR5c, (CH2)rSR5d, (CH2)rCH(xe2x95x90NR5b)NR5bR5c, (CH2)rSO2NR5bR5c, (CH2)rSO2NR5bR5c, (CH2)r(CF2)rCF3 and (CH2)r-phenyl substituted with 0-3 R5e;
R5b and R5c are independently selected at each occurrence from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)r-phenyl;
R5d is independently selected at each occurrence from C1-6 alkyl, phenyl substituted with 0-2 R5e, and benzyl substituted with 0-2 R5e;
R5e is independently selected at each occurrence from hydrogen, xe2x80x94(CH2)rOR5f, halo, C1-4 alkyl, CN, NO2, and xe2x80x94CF3;
R5f is selected from hydrogen and C1-5 alkyl;
R5g is C1-5 alkyl;
n is selected from 1, 2, and 3;
r is selected from 0, 1, and 2.
[7] In a preferred embodiment, the present invention provides novel compounds, wherein:
R1 is phenyl substituted with 1-3 R1a;
R1a is selected from halo, xe2x80x94CN, xe2x80x94CF3 and xe2x80x94CF2CF3;
A is selected from phenyl substituted with 0-3 R5, napthyl substituted with 0-3 R5 and napthyl fused to ring B substituted with 0-3 R5;
X is selected from xe2x80x94C(O)xe2x80x94 and xe2x80x94S(O)2xe2x80x94;
R5 is independently selected at each occurrence from C1-5 alkyl, halo and xe2x80x94OCH3; and
n is selected from 1 and 2.
[8] In a more preferred embodiment, the present invention provides novel compounds, wherein:
R1 is phenyl substituted with 1-2 R1a;
R1a is selected from para-halo and meta-halo;
A is phenyl substituted with 0-3 R5;
X is selected from xe2x80x94C(O)xe2x80x94 and xe2x80x94S(O)2xe2x80x94;
R5 is independently selected at each occurrence from C1-5 alkyl, halo and xe2x80x94OCH3; and
n is selected from 1 and 2.
[9] In a further more preferred embodiment, the present invention provides a compound selected from the group:
2-((1-(4-Fluorophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline,
2-((1-(3-Fluorophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline,
2-((1-(3-Fluorophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline,
2-((1-(4-Pyridylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydro-isoquinoline,
2-((1-(3-Pyridylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydro-isoquinoline,
2-((1-(4-Nitrophenylsulfonyl)-4-piperidyl))-1,2,3,4 tetrahydroisoquinoline,
2-((1-(3-Nitrophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline,
2-((1-(2-Thienylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydro-isoquinoline,
2-((1-(3-Thienylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydro-isoquinoline,
1,3-Dihydro-2-((1-(3-thienylsulfonyl)-4-piperidyl)) isoindole,
1,3-Dihydro-2-((1-(2-thienylsulfonyl)-4-piperidyl)) isoindole,
1,3-Dihydro-2-((1-(4-fluorophenylsulfonyl)-4-piperidyl)) isoindole,
1,3-Dihydro-2-((1-(3-fluorophenylsulfonyl)-4-piperidyl)) isoindole,
1,3-Dihydro-2-((1-(4-nitrophenylsulfonyl)-4-piperidyl)) isoindole,
1,3-Dihydro-2-((1-(3-nitrophenylsulfonyl)-4-piperidyl)) isoindole,
1,3-Dihydro-2-((1-(4-pyridylsulfonyl)-4-piperidyl)) isoindole, and
1,3-Dihydro-2-((1-(3-pyridylsulfonyl)-4-piperidyl)) isoindole,
or a pharmaceutically acceptable salt form thereof.
[10] In a third embodiment, the present invention provides for a novel compound of formula (III): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
R1 is selected from a C6-10 carbocyclic aromatic residue substituted with 1-3 R1a, and a 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, substituted with 0-2 R1a;
R1a is independently selected at each occurrence from (CH2)rOR1d, halo, C1-4 alkyl, (CH2)rxe2x80x94C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCF3, (CH2)rNR1bR1c, (CH2)rSO2R1d, (CH2)rC(O)OH, (CH2)rC(O)OR1d, (CH2)rOC(O)R1d, (CH2)rC(O)R1d, (CH2)rNR1bC(O)R1c, (CH2)rC(O)NR1bR1c, (CH2)rSR1d, (CH2)rCH(xe2x95x90NR1b)NR1bR1c, (CH2)rSO2NR1bR1c, (CH2)rSO2NR1bR1c, (CH2)r(CF2)rCF3 and (CH2)r-phenyl substituted with 0-3 R1e;
R1b and R1c are independently selected at each occurrence from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl and (CH2)r-phenyl substituted with 0-3 R1e;
R1d is independently selected at each occurrence from C1-6 alkyl and (CH2)r-phenyl substituted with 0-2 R1e;
R1e is independently selected at each occurrence from H, xe2x80x94(CH2)rOR1f, halo, C1-4 alkyl, CN, NO2, and xe2x80x94CF3;
R1f is selected from hydrogen and C1-5 alkyl;
R1g is C1-5 alkyl;
R4 is selected independently at each occurrence from hydrogen, C1-6 alkyl, (CH2)rxe2x80x94C3-7 cycloalkyl, (CH2)r-aryl, and (CH2)r-heteroaryl;
R4a is taken together with R1 to form a 5 or 6- membered fused heterocyclic ring containing 1-2 heteroatoms selected from O and N substituted with 1 or 2 carbonyl groups;
R6 is selected independently at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)rxe2x80x94C3-6 cycloalkyl, (CH2)r-phenyl, xe2x80x94OH, xe2x80x94OC(O)R6a, C(O)R6a, C(O)OR6a;
R6a is selected independently from C1-6 alkyl, phenyl and benzyl;
R7 is selected from hydrogen and C1-5 alkyl;
Y is C1-3 alkylene;
A is selected from a 5 or 6 membered saturated, partially saturated or unsaturated ring which contains from 0-1 heteroatoms selected from N, O and S, substituted with 0-3 R5, napthyl substituted with 0-3 R5, and napthyl fused with ring B substituted with 0-3 R5;
R5 is selected independently at each occurrence from (CH2)rOR5d, halo, C1-4 alkyl, (CH2)rxe2x80x94C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCF3, (CH2)rNR5bR5c, (CH2)rSO2R5d, (CH2)rC(O)OH, (CH2)rC(O)OR5d, (CH2)rOC(O)R5d, (CH2)rC(O)R5b, (CH2)rNR5bC(O)R5c, (CH2)rC(O)NR5bR5c, (CH2)rSR5d, (CH2)rCH(xe2x95x90NR5b) NR5bR5c, (CH2)rSO2NR5bR5c, (CH2)rSO2NR5bR5c, (CH2)r(CF2)rCF3 and (CH2)r-phenyl substituted with 0-3 R5e;
R5b and R5c are independently selected at each occurrence from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)r-phenyl;
R5d is independently selected at each occurrence from C1-6 alkyl, phenyl substituted with 0-2 R5e, and benzyl substituted with 0-2 R5e;
R5e is independently selected at each occurrence from hydrogen, xe2x80x94(CH2)rOR5f, halo, C1-4 alkyl, CN, NO2, and xe2x80x94CF3;
R5f is selected from hydrogen and C1-5 alkyl;
R5g is C1-5 alkyl;
n is selected from 1, 2, and 3;
r is selected from 0, 1, and 2; and
m is selected from 1, 2, and 3.
[11] In a preferred embodiment, the present invention provides for novel compounds, wherein:
R1 is phenyl substituted with 1-3 R1a;
R1a is selected independently at each occurrence from halo, xe2x80x94CN, xe2x80x94CF3 and xe2x80x94CF2CF3;
Y is propylene;
A is selected from phenyl substituted with 0-3 R5, napthyl substituted with 0-3 R5 and napthyl fused to ring B substituted with 0-3 R5;
R5 is selected independently at each occurrence from C1-5 alkyl, halo and xe2x80x94OCH3;
n is selected from 1 and 2; and
m is 1.
[12] In a more preferred embodiment, the present invention provides for novel compounds, wherein:
R1 is phenyl substituted with 1-2 R1a;
R1a is selected from para-halo and meta-halo;
A is phenyl substituted with 0-3 R5;
Y is C1-3 alkylene;
R5 is independently selected at each occurrence from C1-5 alkyl, halo and xe2x80x94OCH3; and
n is selected from 1 and 2; and
m is 1.
[13] In a more preferred embodiment, the present invention provides for novel compounds, wherein:
1,3-Dihydro-2-[3-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl)) propyl]isoindole,
1,3-Dihydro-2-[3-((2-(4-bromophenyl)-1,3-dioxolan-2-yl)) propyl]isoindole,
1,3-Dihydro-2-[3-((2-(4-methylphenyl)-1,3-dioxolan-2-yl)) propyl]isoindole, and
2-[3-((2-(4-Fluorophenyl)-1,3-dioxolan-2-yl))propyl]-1,2,3,4-tetrahydroisoquinoline.
In a fourth embodiment, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
In a fifth embodiment, the present invention provides a method of treating a central nervous system disorder, including sleep disorders, depression and schizophrenia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., R1a) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R1a, then said group may optionally be substituted with up to two R1a groups and R1a at each occurrence is selected independently from the definition of R1a. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-6 alkylxe2x80x9d, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
As used herein, xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo, and iodo.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 6- or 10-membered monocyclic or bicyclic aromatic compound. Examples of such carbocycles include phenyl, indanyl, indenyl and naphthyl.
As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d or xe2x80x9caromatic heterocyclexe2x80x9d is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of such aromatic heterocyclic systems include, but are not limited to, pyridyl, pyrimidyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl and indazolyl.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amine prodrugs the amine group is attached to a group selected from OH, C1-4 alkoxy, C6-10 aryloxy, C1-4 alkoxycarbonyl, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, and C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl. More preferred prodrugs are OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of Formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
Some compounds of Formula 1 may be prepared, as shown in Scheme 1, by treatment of an alkylating agent (1-1) with an amine (1-2) in the presence of a base in an appropriate solvent. 
Examples of useful alkylating agents (1-1) are those where LG is a good leaving group, such as Cl, Br, I, alkylsulfonate, arylsulfonate, or perhaloalkylsulfonate. Useful bases include, but are not limited to, an excess of amine (1-2) itself, metal carbonates such as K2CO3 or Cs2CO3, metal hydroxides such as NaOH or KOH, hindered alkoxides such as potassium t-butoxide, or non-nucleophilic tertiary organic amines such as N,N-diisopropylethylamine. These bases are required to absorb the acid Hxe2x80x94LG which is liberated during the reaction. Typical solvents include polar aprotic liquids such as DMF or THF, or protic liquids such as alcohols, including ethanol or isopropanol. It is known by those skilled in the art that the rates of alkylations of amines may be enhanced, particularly where LG is Cl or Br, by the addition of a catalytic amount of an iodide salt, such as NaI or KI, typically in the amount of 0.1 to 5 mole percent.
An alternate set of useful amine alkylation conditions utilize an organic solvent which is poorly miscible with water, such as toluene or dichloromethane, and an aqueous solution of the base, particularly metal alkoxides, along with a phase transfer catalyst (PTC). Typical phase transfer catalysts include tetraalkylammonium halides or hydroxides.
Alternatively, amine (1-1) may be initially converted into its conjugate base by treatment with a strong base, such as n-butyllithium, in an inert solvent, typically THF, near or below ambient temperature under an inert atmosphere such as nitrogen or argon. The resulting amine amion is then treated with alkylating agent (1xe2x80x941), which may be introduced in an inert solvent.
In order to achieve useful reaction rates, any of the above reactions of Scheme 1 may require the application of heat from an external source.
The required alkylating agents (1xe2x80x941), when not commercially available, are generally well known to those skilled in the art and are readily prepared by usual methods. In certain instances, it may be advantageous to prepare reagents (1xe2x80x941) in the same reaction vessel to be used for the alkylation without purification or isolation, before addition of the amine (1-2).
Many examples of the needed amine reagents (1-2) are commercially available or are known in the literature. When the desired amine (1-2) is new, a number of literature methods are generally applicable. These include, but are not limited to, reduction of amides or imides with borane (Gawley et al., J. Org. Chem. 1988, 53, 5381) or lithium aluminum hydride (Uffer et al., Helv. Chim. Acta 1948 31, 1397; Moffett, Org. Syn., Coll. Vol. IV 1963, 354).
An alternate sequence for the synthesis of some compounds of Formula 1 is illustrated in Scheme 2. 
An imide (2-1) is converted to its conjugate base by treatment with a base in an appropriate silvent, then allowed to react with alkylating agent (1-1) described in Scheme 1. An alkyl imide (2-2) intermediate is formed and isolated. The conjugate base of imide (2-1) may be isolated and purified in some instances, such as by precipitation by a non-polar solvent followed by filtration. Useful bases include metal alkoxides and carbonates. Alternatively, this conjugate base may be generated in situ by mixing with a non-nucleophilic base either before or after the addition of the alkylating agent (1-1).
The alkyl imide intermediate (2-2) is then converted to the amine (1) by treatment with a reducing agent, such as borane or lithium aluminum hydride, in an appropriate solvent, typically THF.
It will be recognized by those skilled in the art that certain functional group substituents on reagents (1-1) or (2-1) may not be compatible with the strongly reducing conditions described in Step 2 of Scheme 2. In such instances, these functional groups may be carried through the reaction sequence in a protected form, then released after the reduction reaction. The choice of protecting groups, and conditions for their introduction and subsequent removal, will be known to those skilled in the art, and are generally as described in Green and Wuts, Protective Groups in Organic Synthesis, 2nd Ed., Wiley and Sons, NY, 1991.
Where convenient, some compounds of Formula (I) may be prepared as shown in Scheme 3. 
Here, the functional group Xxe2x80x94H of reagent (3-1) is converted into its nucleophilic conjugate base by treatment with an appropriate base in a useful solvent, and allowed to react with an electrophile (3-2) wherein the leaving group LG, as described above, is connected by linker group Y to the ring nitrogen. The ring nitrogen is rendered in non-nucleophilic form in (3-2) by its incorporation into an amide or imide functional group as shown. The resulting amide or imide adduct (3-3) is then reduced to the desired amine (1) as described in Scheme 2.
The choice of base for the first reaction of Scheme 3 is dependent on the acidity of functional group Xxe2x80x94H of (3-1). Where Xxe2x80x94H of (3-1) is relatively acidic, such as xe2x80x94Sxe2x80x94H, a fairly weak base such as a metal carbonate or hydroxide, is appropriate. For less acidic Xxe2x80x94H such as xe2x80x94Oxe2x80x94H, a stronger base such as metal hydride (e.g. sodium hydride) or alkyllithium will be useful.
The synthesis of the required electrophile (3-2) is by conversion of amide or imide (2-1) to its conjugate base and treatment with bifunctional reagent LGxe2x80x94Yxe2x80x94LG, wherein LG is a leaving group as described above. The two leaving groups may be the same, in which case an excess of the reagent would be employed to statistically ensure monoadduct (3-2), or different, whereby a stoichiometric amount is acceptable and the less reactive LG would remain in (3-2). In some instances the electrophile (3-2) may be prepared in situ and not isolated or purified, but then allowed to react with nucleophile (3-1) as just described. In such an in situ preparation of the electrophile, it may be necessary to preform the conjugate base of reagent (3-1) in a separate reaction vessel, then transfer it into the vessel containing the electrophile.
Another method useful for the preparation of some compounds of Formula 1 is shown in Scheme 4. 
Amine (1-2) is condensed with an aldehyde or ketone (4-1) to form an enamine intermediate, which frequently is not isolated but is reduced in situ to form amine adduct (1). Many such reductive amination conditions are well known in the chemical literature by those skilled in the art, and these are not further detailed here.
Another method for the preparation of some members of Formula 1 is given in Scheme 5. 
Amine (1-2) is condensed with carboxy compound (5-1) to form amide (5-2). The amide is then treated with a reducing agent, commonly borane or lithium aluminum hydride as described earlier, to generate the desired amine (1).
The carboxy group can be the parent carboxylic acid (Z is OH) in which case a coupling reagent must also be used. Many coupling reagents are known in the literature for forming amide bonds from carboxylic acids and amines; examples include, but are not limited to DCC, HBTU, TBTU, HATU, BOP, PyBOP, and alkyl chloroformates. Some of these coupling reagents, such as alkyl chloroformates, also require the presence of a non-nucleophilic base to consume the acid formed. Appropriate bases for such coupling reactions include tertiary amines such as N,N-diisopropylethylamine, triethylamine, or N-methylmorpholine. Under coupling conditions such as these, the carboxy group is converted into an activated species (Z is a leaving group) which is usually not isolated, but is allowed to react in situ with the amine partner (1-2).
Alternatively to the in situ activation of the carboxylic acid for coupling, the acid can be converted into a relatively stable, activated derivative which is isolable in pure form. Examples of this type include, but are not limited to, formation of an acid halide (X is F, Cl, Br), an N-hydroxysuccinimide ester, or a pentafluorophenyl ester. Carboxylic acid pre-activating methods such as these are well known, especially in the peptide literature.
It will be recognized by those skilled in the art that one type of functional group substituent on a compound of Formula 1 may be converted into another functional group by the appropriate chemical reaction at an advantageous point in the synthetic sequence after the ring nitrogen to carbon bond formation in the Schemes is complete. Of course, such manipulations must be chemically compatible with the newly formed tertiary amine present in the compound of Formula 1.
Typically, the free base amine products of Formula 1, once prepared, are treated with an acid in an appropriate solvent to yield a salt adduct. These salt forms are often advantageous because they generally exhibit improved crystallinity, formulatability, and water solubility relative to the parent amines. Frequently, the salt adducts crystallize directly from the salt formation solvent medium, and can be isolated by filtration. In some cases, a co-solvent, usually of lesser polarity, must be added to induce crystallization.
The following examples further illustrate details for the preparation of the compounds of the present invention, and are not to be construed as limiting the inventors scope. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can alternatively be used to prepare compounds of the present invention. All temperatures are degrees Celsius.